WO2001093948A2 - Diagnosis and classification of disease and disability using low frequency magnetic field designed pulses (cnps) - Google Patents

Diagnosis and classification of disease and disability using low frequency magnetic field designed pulses (cnps) Download PDF

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Publication number
WO2001093948A2
WO2001093948A2 PCT/CA2001/000828 CA0100828W WO0193948A2 WO 2001093948 A2 WO2001093948 A2 WO 2001093948A2 CA 0100828 W CA0100828 W CA 0100828W WO 0193948 A2 WO0193948 A2 WO 0193948A2
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subject
physiological function
cnps
disease
change
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PCT/CA2001/000828
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French (fr)
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WO2001093948A3 (en
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Alex W. Thomas
Frank S. Prato
Kevin Patrick White
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Lawson Research Institute
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Priority to CA002410464A priority Critical patent/CA2410464A1/en
Priority to AU2001265728A priority patent/AU2001265728A1/en
Publication of WO2001093948A2 publication Critical patent/WO2001093948A2/en
Publication of WO2001093948A3 publication Critical patent/WO2001093948A3/en
Priority to US10/319,944 priority patent/US7280861B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7235—Details of waveform analysis
    • A61B5/7264—Classification of physiological signals or data, e.g. using neural networks, statistical classifiers, expert systems or fuzzy systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4005—Detecting, measuring or recording for evaluating the nervous system for evaluating the sensory system
    • A61B5/4023—Evaluating sense of balance
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems

Definitions

  • the invention relates to magnetic fields and in particular, to the use of magnetic fields for the diagnosis and classification of disease in both human and veterinarian medicine.
  • Simple pulsed magnetic fields with very high time changing magnetic fields (10,000Tesla/s) (Barker et al., 1987) have been used for the stimulation of nerves (depolarisation and induction of action potential) and for the treatment of primarily affective disorders.
  • These pulses are, in general, simple unipolar or bipolar pulses which are designed to induce currents in nerves and, in themselves, do not carry information as a function of time within each pulse sequence nor can the pulses be used for any diagnostic classification.
  • UK Patent Application 2 270 000 discloses a magnetic field induction therapy apparatus for the therapeutic treatment of pain and the alleviation of circulatory and respiratory problems.
  • U.S. Patent 3,678,337 discloses an apparatus to be used indoors to generate magnetic fields to stimulate natural displacement currents in humans and thus generate general beneficial effects in such humans.
  • U.S. Patent 5,066,272 discloses the use of magnetic pulses which are capable of inducing eddy currents in nearby brain tissue of sufficient strength and duration to cause tissue stimulation and disruption of high level cognitive function and, therefore, are useful in performing functional mapping of the brain. The pulses can also stimulate peripheral nerves and provide measurements of nerve conduction velocity for certain disease diagnosis or motor evoked potentials for surgical monitoring.
  • U.S. Patent 5,935,054 discloses the use of weak externally applied magnetic fields for influencing the nervous system of a subject and in particular, as an aid to relaxation, sleep or arousal and clinically for the control of tremors, seizures and emotional disorders.
  • Cnps specific low frequency pulsed magnetic fields
  • the present invention provides methods of differential diagnoses of diseases in humans and animals which is rapid, safe, non-invasive, objective and well-tolerated.
  • the methods of the invention result in a highly sensitive and specific classification of disease such as but not limited to diseases and health states associated with acute or chronic pain, fatigue or disability.
  • the methods involve short duration exposures to relatively weak and safe magnetic fields (i.e. Cnps) to perturb human or animal cognition or physiological (below the limit of conscious sensory detection) responses.
  • the physiological responses are measured either during the Cnp exposure or after the end of the exposure and represent the effects of this exposure.
  • the physiological perturbation is then objectively and/or subjectively analyzed and used for the diagnostic classification of disease.
  • Cnps generally applied or targeted to a specific body part or tissue of a subject, affect a physiological function.
  • the change in the physiological function can then reliably be used to diagnose whether the subject is suffering from a disease condition.
  • the change in the physiological function or functions can be assessed objectively and/or subjectively and still provide a diagnosis for a disease condition.
  • the method includes the design of a magnetic field (Cnps) which targets specific tissue by its specific waveform design. Localisation can also be enhanced by use of magnetic field generation devices which localise the patient's exposure in 3D space predominantly to target tissue. A whole-body exposure can still target the CNS rather than the peripheral nervous system if the Cnps pulse sequence (the variations in time of the magnetic field) has characteristics of the CNS rather than the peripheral nervous system.
  • the invention provides a method of disease diagnosis using specifically designed pulsed magnetic field (Cnps. such as those described in U.S. Patent No: 6,234,953, the entirety of which is incorporated herein by reference). Furthermore, such Cnps may also be altered by the addition of ultra low frequency (near 0 to 0.1 Hz) components placed as time- varying periods spaced between repetitions of the pulse train. More particularly, the invention relates to the exposure of targeted tissue to Cnps and the assessment of the resulting perturbation of a measured selected physiological response. Differences in these measured physiological responses are subjectively and/or objectively used to determine patient pathology.
  • Cnps specifically designed pulsed magnetic field
  • Cnps for the diagnosis of a disease condition in a subject.
  • Cnps in accordance with another aspect of the present invention is the use of Cnps in a method for the diagnosis of the severity of a disease condition in a subject. It is understood that the subject may be a human or animal subject.
  • Cnps in accordance with another aspect of the present invention is the use of Cnps in a method for the diagnosis of various disease conditions in humans or animals.
  • the Cnps may be targeted to a specific tissue or body portion.
  • the physiological function may be a motor or cognitive function.
  • a method for the diagnosis of disease conditions in a subject comprising; exposing a subject to a Cnps; - simultaneously monitoring a selected physiological function; evaluating a change in the selected physiological function; assessing said change in the selected physiological function; and classifying the subject into a disease category.
  • a method for the diagnosis and assessment of disease conditions in a subject comprising:
  • a method for the diagnosis and assessment of disease conditions in a subject comprising; - exposing a subject to a first selected Cnps while monitoring a selected physiological function;
  • a method for the diagnosis of disease conditions in a subject comprising; - evaluating a selected physiological function in a subject;
  • a method for the diagnosis of disease conditions in a subject comprising; - exposing a subject simultaneously to two or more selected Cnps while monitoring at least one selected physiological function;
  • the methods of the present invention may be used for the separation of patients with fibromyalgia and other acute and chronic central (neurogenic) pain states from those with rheumatoid arthritis and other acute and chronic peripheral (non-neurogenic) pain states.
  • Various central disorders may also be diagnosed using the present method.
  • the method may be used for the separation of patients with moderate to severe pain from those feigning pain; for separation of patients with moderate to severe fatigue from those feigning fatigue; and for separation of patients with moderate to severe disability related to pain and/or fatigue from those feigning disability.
  • the novel method allows for the assessment of the severity of certain disease conditions.
  • Physiological functions monitored in the method of the invention include but are not limited to standing balance, electrical activity in the brain, heart rate and rhythm, respiration, skin temperature, eye movements, cognition, memory, learning, vision or speech.
  • Subjective functions evaluated in the method of the invention include but are not limited to the extent of pain, extent of discomfort, extent of depression, extent of unpleasantness, extent of anxiety, extent of uneasiness, extent of excitement, extent of arousal, extent of attention and extent of suggestability.
  • One skilled in the art would understand the scope and subjective functional assessment that can be effectively used in the methods of the present invention.
  • the method of the present invention also has utility for the determination of an objective measure of pain, fatigue and/or disability in a subject during normal activity or following exercise or repetitive tasks.
  • a further aspect of the present invention is a method of objectively measuring pain, fatigue and/or disability in a subject, the method comprising: - exposing a subject to a selected Cnps; simultaneously monitoring a selected physiological function; comparing the physiological function with that of a suitable control; classifying the subject as experiencing pain, fatigue and/or a disability of feigning pain, fatigue and/or a disability.
  • a further aspect of the present invention is the use of Cnps for altering a physiological function in order to detect early stages of various disease conditions.
  • the method of the present invention serves as an objective assay leading to the separation of sub-classes of physical and behavioural pathologies in humans or animals.
  • the method can be used as a prognosis or predictive indicator of a change in a physical pathology in either humans or animals.
  • a system for the diagnosis of disease conditions in a subject comprising;
  • Figure 1 illustrates a schematic diagram of the 3-D Helmholtz coil array magnetic field exposure and behavioral monitoring system.
  • Figure 2 shows a subject positioned within the magnetic field exposure system which includes three nested orthogonal Helmholtz coils (2 m, 1.75 m and 1.5 m diameter) wound on moveable Lexan® frames showing the coil array partially closed. The wheel track is shown in place (see A). During coil movement, the lower Z axis coil will be locked to the upper coil on the left side, permitting the subject to remain comfortably in a standing position throughout the protocol. For demonstration purposes only, the subject's right hand indicates the raised side of the lower Z axis coil.
  • Figure 3 shows raw forceplate data recorded real-time for blinded processing and analysis at a later time.
  • the preliminary center of pressure (COP) is shown with data projected perpendicular through the forceplate with the line representing movement over time.
  • Subjects, blind to the exposure condition, stand in the center of a forceplate mounted level to the surface of a sub-floor with feet slightly apart at a prescribed distance are randomly exposed to either a Sham or PEMF condition with either eyes-open or eyes-closed.
  • Figure 4 shows a graph of Standing Balance Movement which represents an estimate of the cumulative amount of movement during normal standing.
  • the center of pressure (COP) is projected vertically through the force plate, and the distance from the normalized center of standing pressure to each x-y coordinate (20 samples per second for each of the four 2 min trials) is summed to produce a 'Line' value in meters.
  • COP center of pressure
  • Figure 5 shows a graph comparing the "Romberg Quotient (RQ)" (represents an estimate of the cumulative pattern of movement during normal standing balance (Sham vs PEMF exposed), with the 'eyes closed' condition divided by the 'eyes open' condition) in normals, fibromyalgia and rheumatoid arthritis patients.
  • the center of pressure (COP) is projected vertically through the force plate, and the distance from the normalized center of standing balance of each x-y coordinate (20 samples per second for each of the four 2 min trials) is summed to produce a value in meters.
  • Figure 6 is a graph illustrating the "Romberg Quotient (RQ)" representing a total distance of movement during normal standing balance (Sham vs PEMF exposed), with the 'eyes closed' condition divided by the 'eyes open' condition.
  • the center of pressure (COP) is projected vertically through the force plate. This point is then traced to record the total length of the wandering path of movement around the normalized center of standing balance to each x-y coordinate (20 samples per second for each of the four 2 min trials) is summed to produce a 'Path length' in meters.
  • Figure 7A is a graph illustrating a "Line” representing an estimate of the 'pattern' of movement during normal standing balance (Sham versus PEMF exposed) for subjects under two different light conditions.
  • the center of Pressure (COP) is projected vertically through the force plate, and the distance from the normalized center of standing balance to each x-y coordinate (10 samples per second for each of the four 2 min trials) is summed to produce a 'Line' length value in meters.
  • Figure 7B is a graph illustrating a pattern of sway, as quantified using "line” (sum of line segment lengths) for subjects under two different light intensities, with eyes open and eyes closed, and sham exposed or PEMF exposed.
  • Figure 8A is a graph illustrating the "Romberg Quotient (RQ)" which represents an estimate of the cumulative area of movement during normal standing balance (Sham versus PEMF exposed), with the 'eyes closed' condition divided by the 'eyes open' condition for subjects under two different light conditions.
  • the center of pressure (COP) is projected vertically through the force plate and the pattern of movement around the normalized center of standing balance to each x-y coordinate (10 samples per second for each of the four 2 min trials) is summed to produce a value in meters.
  • Figure 8B is a graph illustrating the "Romberg Quotient (RQ)" +/- SEM (eyes closed/eyes open) indicating that the typical increase in movement which occurs when eyes are closed is similar for sham exposures under both light intensities. However, when exposed to PEMF's, the RQ significantly (p ⁇ 0.005) increased under the low light (0.12 W/m 2 ) condition and was non-significant under the high light (0.51 W/m 2 ) condition.
  • Figure 9 shows that Cnps are modified to produce a 'pulse train' of Cnps spaced in time to alter the frequency spectra such that the effect of the general Cnps is to target the functioning of specific tissues in the organism.
  • FIG. 10 is a graph illustrating real-time spectral analysis of the 'light level' conditions (high vs. low flourescent light levels) (McMahan LightSpex, NC). Light levels were recorded in a 'horizontal' attitude by pointing the recording device in the same direction as a subject's eye, from the same position in the apparatus or typical office working position.
  • the present invention may be used to diagnoses any type of disease state having an impact on motor or cognitive function such as for example but not limited to, Parkinson's, Huntington's chorea, Multiple Sclerosis (MS) and other central nervous system disorders. Peripheral disorders such as rheumatoid arthritis, those associated with diabetes and muscular dystrophy may also be diagnosed and assessed using the method of the present invention.
  • Parkinson's Huntington's chorea
  • MS Multiple Sclerosis
  • Peripheral disorders such as rheumatoid arthritis, those associated with diabetes and muscular dystrophy may also be diagnosed and assessed using the method of the present invention.
  • the method of the present invention employs a 3-D Helmholtz coil array magnetic field exposure and behavioral monitoring system as is shown in Figure 1.
  • This system includes a forceplate, cameras and coil array housed in one room.
  • Techron amplifiers and signal conditioners are housed in a separate but attached equipment closet and computers and control/monitoring equipment are housed in a separate but attached lab/office. It is understood that variations to the set up of this system can be made without affecting its integrity or functioning.
  • the patient is placed within a volume coil which produces a uniform magnetic field (Cnps) throughout a specified portion of the patient's anatomy, such as for example, the head.
  • the volume coil is sufficiently large that it exposes the entire patient's body to substantial magnetic fields.
  • this readout device is a 3D forceplate (OR6-7-1000, AMI, Watertown MA). It is understood by those skilled in the art that other devices/methods could be just as effective and thus used as a readout device such as for example an EEG array, a SQUID array or a multi-lead ECG.
  • the important feature for the selected readout device is that it be able to record a physiological phenomenon that is to be perturbed by the magnetic field exposure.
  • the 3D forceplate provides a measure of standing balance that is an outcome of the state of functioning of the vestibular system. If the vestibular system is negatively affected ("one gets dizzy"), standing balance deteriorates and the movement of the center of mass increases.
  • the Cnps is designed to target the vestibular system and hence standing balance is - ⁇
  • the target of the Cnps is another system, such as the visual system and an outcome associated with vision is thus measured (Prato et al., 2001).
  • the patient is then exposed to a desired Cnps.
  • An example of the one used to target the vestibular system is shown in Figure 9. It is not necessary and in fact it is preferred that a volume coil not touch the patient as magnetic fields can penetrate tissue without direct contact with the volume coil. It is also preferred that the magnetic field exposure be monitored to ensure that the prescribed pulsed magnetic field (Cnps) is actually produced by the volume coil (Thomas et al, 2001a).
  • the exposure protocol has the subject standing on the forceplate in the centre of the exposure system such that the uniform magnetic field of the volume coil is centred at head level. It is preferred that subjects stand with their feet slightly apart (approximately 15cm) in the centre of the 3D forceplate with all forceplate values continually digitally recorded at 10 samples per second throughout the randomly assigned four 2-minute exposures (see Figure 9).
  • objective or subjective measures may be made after the end of exposure to the Cnps and compared to a baseline measurement made prior to exposure.
  • Table 2 it is demonstrated that the sway perturbing Cnps produces a different result when comparing rheumatoid arthritis (RA) patients to fibromyalgia (FM) patients for the subjective measure of "how bad is your pain RIGHT NOW?" and "how bad is your stiffness RIGHT NOW?".
  • the type of disease may be diagnosed and the severity of the disease diagnosed by comparing differential physiological effects from two different Cnps exposures.
  • mice exposed to a postural sway altering Cnps results in different effects on different behaviours as compared to mice exposed to an analgesia-inducing Cnps as seen in Table 4 (Choleris et al, 2001).
  • analgesia-inducing Cnps as seen in Table 4 (Choleris et al, 2001).
  • differential physiological effects occur in normal human subjects when exposed to different Cnps and that for the same Cnps, human patients with different diseases respond differently (Thomas et al, 2001c).
  • the type of disease and severity of the disease may be diagnosed by comparing differential physiological effects from the same Cnps but under two different environmental conditions such as different light conditions.
  • two different environmental conditions such as different light conditions.
  • there are different responses under different light conditions to the same Cnp Prato et al, 2001.
  • 5 and 6 there are different responses to the same Cnp in patients with different underlying diseases (Thomas et al., 2001c).
  • diagnostic specificity and/or sensitivity should increase.
  • the type of and severity of the disease maybe diagnosed by comparing differential physiological effects from the same or different Cnps while being imaged with devices such as but not limited to functional magnetic resonance imaging (FMRI), position emission tomography (PET or SPECT), magnetoencephalography (MEG), electromyography (EMG) or electroencephalography (EEG).
  • FMRI functional magnetic resonance imaging
  • PET position emission tomography
  • MEG magnetoencephalography
  • EMG electromyography
  • EEG electroencephalography
  • Outcome measures are then analysed in a manner relevant to the Cnps targeted tissue.
  • the measurements of the forceplate can be represented as a number of relevant parameters such as: total path, total area, total line and the total line can be broken down into the individual horizontal directions Table 1 and 3.
  • Figure 4 shows typical measures of line (in metres) for three groups of human subjects: normals, patients with rheumatoid arthritis (RA) and patients with fibromyalgia (FM).
  • Figure 5 shows how the outcome measures must be analysed such that the one sensitive to Cnps exposure is properly quantified.
  • the 'Romberg Quotient' shows that the vestibular system is perturbed by the PEMF but not the Sham exposure.
  • FIGS 7A/B, 8A/B and 10 show the results from human subjects exposed to different light intensities. In the 9 normal subjects (mean age 26.4 (sd 2.6); 6 male, 3 female) exposed to a light intensity of 0.12W/m 2 , statistical analysis of the data (analysis of variance) indicated that there was a significant increase in standing movement during PEMF during eyes closed but not during eyes open.
  • the present invention has numerous applications in various industries where the determination and severity of true pain and general disability be identified.
  • RA Rheumatoid Arthritis
  • FM Fibromyalgia
  • Cnps Pulsed Magnetic Fields
  • Figure 3 shows a typical result in one patient with the pattern changing when the subject closes their eyes and when they are exposed to the Cnps.
  • Figures 4, 5 and Figure 6 provide the raw data, the RQ and results for 3 parameter reductions of the raw data.
  • FM patients and controls appeared to have similar standing balance while RA patients had worse standing balance (Figure 4).
  • the RQ was highest among FM patients ( Figure 5, Figure 6).
  • RA and FM patients and healthy controls differed with respect to standing balance and the effect of the Cnps.
  • the separation of RA patients from FM patients is of significant value as these patients are often given the wrong classification, ie. FM patients diagnosed incorrectly as RA patients and vice versa, especially in the initial manifestation of the disease.
  • the ability to separate both these patients from normal controls especially FM from normal controls is extremely important in the scenario of workmen's compensation benefits.
  • individuals without true pain, fatigue or disability can feign pain, fatigue and/or disability and hence, be inappropriately classified as FM patients and receive compensation. It is also possible that true FM patients may not receive compensation as they cannot be objectively categorized.
  • the method of the present invention is entirely objective, it provides for the first time a measure which can be used to determine compensation rights.
  • Ratios of electrical current were applied to the web of the left thumb required to produce a subjective "moderate” pain rating in male and female university students (N ⁇ l l) while exposed to either a sham or pulsed magnetic field (Figure
  • a ratio greater than 1 may be interpreted as an indication of analgesia (or hypoalgesia), and less than 1, hyperalgesia.
  • Barker A.T. Freeston I.L., Jalinous R., Jarratt J.A.. Magnetic stimulation of the human brain and peripheral nervous system: an introduction and the results of initial clinical evaluation. Neurosurgery 1987, 20, 100-109.
  • ⁇ relates to a significant difference (greater than, P ⁇ 0.05) between RA and FM within Pre- or Post-experiment testing
  • t relates to a significant difference (greater than, P ⁇ 0.05) between Pre- and Post-experiment testing.

Abstract

The invention is directed to the use of magnetic field designed pulses for the diagnoses and classification of severity of disease states and disability in humans and animals.

Description

Diagnosis and Classification of Disease and Disability using Low Frequency Magnetic
Field Designed Pulses (Cnps)
Field of Invention
The invention relates to magnetic fields and in particular, to the use of magnetic fields for the diagnosis and classification of disease in both human and veterinarian medicine.
Background of the Invention Studies have suggested that magnetic stimuli can affect behavioral, cellular and physiological functions of animals. As a result magnetic therapy was developed for the therapeutic treatment of pain in humans as well as for the general well-being of humans.
Simple pulsed magnetic fields with very high time changing magnetic fields (10,000Tesla/s) (Barker et al., 1987) have been used for the stimulation of nerves (depolarisation and induction of action potential) and for the treatment of primarily affective disorders. These pulses are, in general, simple unipolar or bipolar pulses which are designed to induce currents in nerves and, in themselves, do not carry information as a function of time within each pulse sequence nor can the pulses be used for any diagnostic classification.
UK Patent Application 2 270 000 discloses a magnetic field induction therapy apparatus for the therapeutic treatment of pain and the alleviation of circulatory and respiratory problems.
U.S. Patent 3,678,337 discloses an apparatus to be used indoors to generate magnetic fields to stimulate natural displacement currents in humans and thus generate general beneficial effects in such humans. U.S. Patent 5,066,272 discloses the use of magnetic pulses which are capable of inducing eddy currents in nearby brain tissue of sufficient strength and duration to cause tissue stimulation and disruption of high level cognitive function and, therefore, are useful in performing functional mapping of the brain. The pulses can also stimulate peripheral nerves and provide measurements of nerve conduction velocity for certain disease diagnosis or motor evoked potentials for surgical monitoring. U.S. Patent 5,935,054 discloses the use of weak externally applied magnetic fields for influencing the nervous system of a subject and in particular, as an aid to relaxation, sleep or arousal and clinically for the control of tremors, seizures and emotional disorders.
None of these prior art references.nor the literature in general, has contemplated or actually demonstrated that pulsed magnetic fields could be used for the diagnostic classification of disease, including diseases and health states associated with acute or chronic pain, fatigue or disability. Furthermore, none of the prior art has suggested or demonstrated the ability to separate patients into different disease categories based on exposure to pulsed magnetic fields. It was previously demonstrated by the present Applicant in U.S. Patent No: 6,234,953
(the entirety of which is hereby incorporated by reference) that specific low frequency pulsed magnetic fields (Cnps) having a plurality of intermittent waveforms could be used in methods for treating physiological, neurological and behavioral disorders. It is now unexpectedly demonstrated that such Cnps can be used for the diagnostic classification of disease.
Summary of the Invention
The present invention provides methods of differential diagnoses of diseases in humans and animals which is rapid, safe, non-invasive, objective and well-tolerated. The methods of the invention result in a highly sensitive and specific classification of disease such as but not limited to diseases and health states associated with acute or chronic pain, fatigue or disability. The methods involve short duration exposures to relatively weak and safe magnetic fields (i.e. Cnps) to perturb human or animal cognition or physiological (below the limit of conscious sensory detection) responses. The physiological responses are measured either during the Cnp exposure or after the end of the exposure and represent the effects of this exposure. The physiological perturbation is then objectively and/or subjectively analyzed and used for the diagnostic classification of disease.
The Applicant has demonstrated that Cnps, generally applied or targeted to a specific body part or tissue of a subject, affect a physiological function. The change in the physiological function can then reliably be used to diagnose whether the subject is suffering from a disease condition. The change in the physiological function or functions can be assessed objectively and/or subjectively and still provide a diagnosis for a disease condition. The method includes the design of a magnetic field (Cnps) which targets specific tissue by its specific waveform design. Localisation can also be enhanced by use of magnetic field generation devices which localise the patient's exposure in 3D space predominantly to target tissue. A whole-body exposure can still target the CNS rather than the peripheral nervous system if the Cnps pulse sequence (the variations in time of the magnetic field) has characteristics of the CNS rather than the peripheral nervous system.
The invention provides a method of disease diagnosis using specifically designed pulsed magnetic field (Cnps. such as those described in U.S. Patent No: 6,234,953, the entirety of which is incorporated herein by reference). Furthermore, such Cnps may also be altered by the addition of ultra low frequency (near 0 to 0.1 Hz) components placed as time- varying periods spaced between repetitions of the pulse train. More particularly, the invention relates to the exposure of targeted tissue to Cnps and the assessment of the resulting perturbation of a measured selected physiological response. Differences in these measured physiological responses are subjectively and/or objectively used to determine patient pathology.
In accordance with an aspect of the present invention is the use of Cnps for the diagnosis of a disease condition in a subject.
In accordance with another aspect of the present invention is the use of Cnps in a method for the diagnosis of the severity of a disease condition in a subject. It is understood that the subject may be a human or animal subject.
In accordance with another aspect of the present invention is the use of Cnps in a method for the diagnosis of various disease conditions in humans or animals. The Cnps may be targeted to a specific tissue or body portion.
In accordance with still a further aspect of the present invention is the use of Cnps to affect a selected physiological function in a subject. The physiological function may be a motor or cognitive function.
In accordance with a further aspect of the present invention is a method for the diagnosis of disease conditions in a subject, the method comprising; exposing a subject to a Cnps; - simultaneously monitoring a selected physiological function; evaluating a change in the selected physiological function; assessing said change in the selected physiological function; and classifying the subject into a disease category. In accordance with another aspect of the present invention is a method for the diagnosis and assessment of disease conditions in a subject, the method comprising:
- exposing a subject simultaneously to a selected Cnps and a first prescribed light intensity and frequency distribution while monitoring a selected physiological function;
- exposing said subject a second time simultaneously to said selected Cnps and a different light intensity of the same or different frequency distribution as said first prescribed light intensity while monitoring a selected physiological function; and
- evaluating any change in the selected physiological function; - assessing said change in the selected physiological function; and
- classifying said subject into a disease category based on the assessment of the change in the selected physiological function.
In accordance with another aspect of the present invention is a method for the diagnosis and assessment of disease conditions in a subject, the method comprising; - exposing a subject to a first selected Cnps while monitoring a selected physiological function;
- exposing said subject a second time to a second selected Cnps while monitoring a selected physiological function;
- evaluating any change in the selected physiological function; - assessing said change in the selected physiological function; and
- classifying said subject into a disease category based on the assessment of the change in the selected physiological function.
In accordance with still another aspect of the present invention is a method for the diagnosis of disease conditions in a subject, the method comprising; - evaluating a selected physiological function in a subject;
- exposing said subject to a selected Cnps;
- evaluating any change in the selected physiological function;
- assessing said change in the selected physiological function; and
- classifying said subject into a disease category based on the assessment of the change in the selected physiological function.
In accordance with another aspect of the present invention is a method for the diagnosis of disease conditions in a subject, the method comprising; - exposing a subject simultaneously to two or more selected Cnps while monitoring at least one selected physiological function;
- evaluating any change in the at least one selected physiological function;
- assessing said change in the at least one selected physiological function; and - classifying said subject into a disease category based on the assessment of the change in the at least one selected physiological function.
The methods of the present invention may be used for the separation of patients with fibromyalgia and other acute and chronic central (neurogenic) pain states from those with rheumatoid arthritis and other acute and chronic peripheral (non-neurogenic) pain states. Various central disorders may also be diagnosed using the present method. Furthermore, the method may be used for the separation of patients with moderate to severe pain from those feigning pain; for separation of patients with moderate to severe fatigue from those feigning fatigue; and for separation of patients with moderate to severe disability related to pain and/or fatigue from those feigning disability. In general, the novel method allows for the assessment of the severity of certain disease conditions.
Physiological functions monitored in the method of the invention include but are not limited to standing balance, electrical activity in the brain, heart rate and rhythm, respiration, skin temperature, eye movements, cognition, memory, learning, vision or speech.
Subjective functions evaluated in the method of the invention include but are not limited to the extent of pain, extent of discomfort, extent of depression, extent of unpleasantness, extent of anxiety, extent of uneasiness, extent of excitement, extent of arousal, extent of attention and extent of suggestability. One skilled in the art would understand the scope and subjective functional assessment that can be effectively used in the methods of the present invention. The method of the present invention also has utility for the determination of an objective measure of pain, fatigue and/or disability in a subject during normal activity or following exercise or repetitive tasks.
According to a further aspect of the present invention is a method of objectively measuring pain, fatigue and/or disability in a subject, the method comprising: - exposing a subject to a selected Cnps; simultaneously monitoring a selected physiological function; comparing the physiological function with that of a suitable control; classifying the subject as experiencing pain, fatigue and/or a disability of feigning pain, fatigue and/or a disability. According to a further aspect of the present invention is the use of Cnps for altering a physiological function in order to detect early stages of various disease conditions. The method of the present invention serves as an objective assay leading to the separation of sub-classes of physical and behavioural pathologies in humans or animals.
In other aspects of the invention, the method can be used as a prognosis or predictive indicator of a change in a physical pathology in either humans or animals.
In yet another aspect of the present invention there is provided a system for the diagnosis of disease conditions in a subject, the system comprising;
- a coil array that produces a uniform magnetic field that perturbs a physiological function in a subject that is quantitatively or qualitatively assessed to generate a data set;
- a data set representing a control;
- wherein the two data sets are comparatively analyzed to classify the subject in a disease category.
In yet another aspect of the invention there is provided a method for the diagnosis and assessment of disease conditions in a subject, the method comprising;
- comparing a data set representing the perturbation of a physiological function in a subject with a data set representing a control; - classifying the subject in a disease category.
Other aspects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from the detailed description.
Brief Description of the Drawings
The invention will now be described in relation to the drawings in which: Figure 1 illustrates a schematic diagram of the 3-D Helmholtz coil array magnetic field exposure and behavioral monitoring system. Figure 2 shows a subject positioned within the magnetic field exposure system which includes three nested orthogonal Helmholtz coils (2 m, 1.75 m and 1.5 m diameter) wound on moveable Lexan® frames showing the coil array partially closed. The wheel track is shown in place (see A). During coil movement, the lower Z axis coil will be locked to the upper coil on the left side, permitting the subject to remain comfortably in a standing position throughout the protocol. For demonstration purposes only, the subject's right hand indicates the raised side of the lower Z axis coil.
Figure 3 shows raw forceplate data recorded real-time for blinded processing and analysis at a later time. The preliminary center of pressure (COP) is shown with data projected perpendicular through the forceplate with the line representing movement over time. Subjects, blind to the exposure condition, stand in the center of a forceplate mounted level to the surface of a sub-floor with feet slightly apart at a prescribed distance are randomly exposed to either a Sham or PEMF condition with either eyes-open or eyes-closed.
Figure 4 shows a graph of Standing Balance Movement which represents an estimate of the cumulative amount of movement during normal standing. The center of pressure (COP) is projected vertically through the force plate, and the distance from the normalized center of standing pressure to each x-y coordinate (20 samples per second for each of the four 2 min trials) is summed to produce a 'Line' value in meters. With eyes open and during sham exposure, FM patients and controls appeared to have similar standing balance, with RA patients having decreased balance. With eyes closed, standing balance worsened from all three groups, but more for RA and FM patients than controls. Mixed design analysis of variance on the center of pressure (COP) movements show a significant interaction of eyes open/closed and sham/PEMF conditions [F=8.78(1.42), PO.006].
Figure 5 shows a graph comparing the "Romberg Quotient (RQ)" (represents an estimate of the cumulative pattern of movement during normal standing balance (Sham vs PEMF exposed), with the 'eyes closed' condition divided by the 'eyes open' condition) in normals, fibromyalgia and rheumatoid arthritis patients. The center of pressure (COP) is projected vertically through the force plate, and the distance from the normalized center of standing balance of each x-y coordinate (20 samples per second for each of the four 2 min trials) is summed to produce a value in meters. The Romberg Quotient was highest amount FM patients. Romberg Quotients of COP movements improve significantly with PEMF exposure [F=9.5(1,42),P<0.005]. Figure 6 is a graph illustrating the "Romberg Quotient (RQ)" representing a total distance of movement during normal standing balance (Sham vs PEMF exposed), with the 'eyes closed' condition divided by the 'eyes open' condition. The center of pressure (COP) is projected vertically through the force plate. This point is then traced to record the total length of the wandering path of movement around the normalized center of standing balance to each x-y coordinate (20 samples per second for each of the four 2 min trials) is summed to produce a 'Path length' in meters. COP path length shows an interaction approaching significance with clinical diagnosis [F=3.2(l,28), PO.09].
Figure 7A is a graph illustrating a "Line" representing an estimate of the 'pattern' of movement during normal standing balance (Sham versus PEMF exposed) for subjects under two different light conditions. The center of Pressure (COP) is projected vertically through the force plate, and the distance from the normalized center of standing balance to each x-y coordinate (10 samples per second for each of the four 2 min trials) is summed to produce a 'Line' length value in meters. Figure 7B is a graph illustrating a pattern of sway, as quantified using "line" (sum of line segment lengths) for subjects under two different light intensities, with eyes open and eyes closed, and sham exposed or PEMF exposed. Sway is increased with eyes closed and PEMF (p<0.005) under low light intensity (0.12W/m2) and decreased (approaching significance, p<0.09) under high intensity light (0.51 W/m2). Figure 8A is a graph illustrating the "Romberg Quotient (RQ)" which represents an estimate of the cumulative area of movement during normal standing balance (Sham versus PEMF exposed), with the 'eyes closed' condition divided by the 'eyes open' condition for subjects under two different light conditions. The center of pressure (COP) is projected vertically through the force plate and the pattern of movement around the normalized center of standing balance to each x-y coordinate (10 samples per second for each of the four 2 min trials) is summed to produce a value in meters.
Figure 8B is a graph illustrating the "Romberg Quotient (RQ)" +/- SEM (eyes closed/eyes open) indicating that the typical increase in movement which occurs when eyes are closed is similar for sham exposures under both light intensities. However, when exposed to PEMF's, the RQ significantly (p<0.005) increased under the low light (0.12 W/m2) condition and was non-significant under the high light (0.51 W/m2) condition. Figure 9 shows that Cnps are modified to produce a 'pulse train' of Cnps spaced in time to alter the frequency spectra such that the effect of the general Cnps is to target the functioning of specific tissues in the organism. The rise time, latency period, refractory period, length of segment sections and number of repetitions per unit time are intrinsic to producing a specific Cnps action, such as altering the function of a specific tissue or group of tissues thus resulting in behavioral change in the organism. In this particular example, standing balance in human subjects was altered to highlight a difference in pain-related pathology, in that, rheumatoid arthritis sufferers differ statistically from fibromyalgia sufferers, and both clinical groups differ from normal controls. Figure 10 is a graph illustrating real-time spectral analysis of the 'light level' conditions (high vs. low flourescent light levels) (McMahan LightSpex, NC). Light levels were recorded in a 'horizontal' attitude by pointing the recording device in the same direction as a subject's eye, from the same position in the apparatus or typical office working position.
Figure 11 is a graph illustrating the ratio of electric current (mA time point/mA baseline) applied to the web of the left thumb required to produce a subjective "moderate pain" rating in male and female university students (N=12) while exposed to either a sham or pulsed magnetic field.
Detailed Description of the Preferred Embodiments It has now been demonstrated that designed Cnps can be used not only for therapeutic treatment of various clinical conditions, but now can also be used for the diagnosis and assessment of a variety of disease conditions some of which are related with pain and/or fatigue and may even be used to diagnose disability as a whole as well as the degree of disability. The use of weak magnetic field pulses to perturb a selected physiological function and recordation of the perturbation for analyses and subsequent disease assessment and diagnoses has not previously been done or suggested. This method has great clinical value in the accurate diagnosis of patients in order to provide for correct and expedient treatment. The present invention has value in the determination of "real pain" in a patient rather than "feigning pain". Both the medical community as a whole and health insurers may greatly benefit from such technology as it may save a tremendous amount of money that could be put to better use in providing health care to those genuinely in need. The present invention may be used to diagnoses any type of disease state having an impact on motor or cognitive function such as for example but not limited to, Parkinson's, Huntington's chorea, Multiple Sclerosis (MS) and other central nervous system disorders. Peripheral disorders such as rheumatoid arthritis, those associated with diabetes and muscular dystrophy may also be diagnosed and assessed using the method of the present invention.
Patient Set-Up
The method of the present invention employs a 3-D Helmholtz coil array magnetic field exposure and behavioral monitoring system as is shown in Figure 1. This system includes a forceplate, cameras and coil array housed in one room. Techron amplifiers and signal conditioners are housed in a separate but attached equipment closet and computers and control/monitoring equipment are housed in a separate but attached lab/office. It is understood that variations to the set up of this system can be made without affecting its integrity or functioning. In the method of the present invention the patient is placed within a volume coil which produces a uniform magnetic field (Cnps) throughout a specified portion of the patient's anatomy, such as for example, the head. In the example shown in Figure 2, the volume coil is sufficiently large that it exposes the entire patient's body to substantial magnetic fields. However, it is consistent with this amplification that smaller volume coils can be used which would encompass only the head or only a desired extremity. In the method of the invention, specifically designed magnetic field pulses are created such as those described in Applicant's U.S. Patent No. 6,234,953.
Once the patient is placed in the volume coil, the patient is then connected to a physiological readout device. As shown in Figure 1, this readout device is a 3D forceplate (OR6-7-1000, AMI, Watertown MA). It is understood by those skilled in the art that other devices/methods could be just as effective and thus used as a readout device such as for example an EEG array, a SQUID array or a multi-lead ECG. The important feature for the selected readout device is that it be able to record a physiological phenomenon that is to be perturbed by the magnetic field exposure. For example, the 3D forceplate provides a measure of standing balance that is an outcome of the state of functioning of the vestibular system. If the vestibular system is negatively affected ("one gets dizzy"), standing balance deteriorates and the movement of the center of mass increases. In one embodiment of the present invention, the Cnps is designed to target the vestibular system and hence standing balance is - ¬
the appropriate outcome measure (Thomas et al., 2001 a,b,c). In a further embodiment of the present invention, the target of the Cnps is another system, such as the visual system and an outcome associated with vision is thus measured (Prato et al., 2001).
Magnetic Field Exposure
Once a patient is set up within the system and a desired physiological function is selected for monitoring, the patient is then exposed to a desired Cnps. An example of the one used to target the vestibular system is shown in Figure 9. It is not necessary and in fact it is preferred that a volume coil not touch the patient as magnetic fields can penetrate tissue without direct contact with the volume coil. It is also preferred that the magnetic field exposure be monitored to ensure that the prescribed pulsed magnetic field (Cnps) is actually produced by the volume coil (Thomas et al, 2001a). In the example of the vestibular system, the exposure protocol has the subject standing on the forceplate in the centre of the exposure system such that the uniform magnetic field of the volume coil is centred at head level. It is preferred that subjects stand with their feet slightly apart (approximately 15cm) in the centre of the 3D forceplate with all forceplate values continually digitally recorded at 10 samples per second throughout the randomly assigned four 2-minute exposures (see Figure 9).
Using a standardised dialogue, subjects are asked to stand looking straight ahead with their eyes open and then be asked to slowly close their eyes, if required. Each of the trials (2 minute trial, eyes open/closed, sham PEMF exposure) ends with a short rest period (approximate 30s). At the end of each rest period (required for the operator to reset the data logger under computer control in a separate room and for the subject to relieve muscle tension), the next randomly assigned trial is initiated using the standardised dialogue. There should be no or minimal PEMF/sham-related cues in the apparatus (Thomas et al, 2000 a) thus ensuring the subject is blind to the exposure condition. hi a further aspect of the present invention, objective or subjective measures may be made after the end of exposure to the Cnps and compared to a baseline measurement made prior to exposure. In Table 2, it is demonstrated that the sway perturbing Cnps produces a different result when comparing rheumatoid arthritis (RA) patients to fibromyalgia (FM) patients for the subjective measure of "how bad is your pain RIGHT NOW?" and "how bad is your stiffness RIGHT NOW?". In still a further embodiment of the present invention the type of disease may be diagnosed and the severity of the disease diagnosed by comparing differential physiological effects from two different Cnps exposures. As seen in Table 5, in mice exposed to a postural sway altering Cnps results in different effects on different behaviours as compared to mice exposed to an analgesia-inducing Cnps as seen in Table 4 (Choleris et al, 2001). As seen in Figure 11, differential physiological effects occur in normal human subjects when exposed to different Cnps and that for the same Cnps, human patients with different diseases respond differently (Thomas et al, 2001c).
In yet a further embodiment of the present invention, the type of disease and severity of the disease may be diagnosed by comparing differential physiological effects from the same Cnps but under two different environmental conditions such as different light conditions. As seen in Figures 7A, 7B, 8A, 8B, 10 and in Table 3, there are different responses under different light conditions to the same Cnp (Prato et al, 2001). As seen in Figures 4, 5 and 6 there are different responses to the same Cnp in patients with different underlying diseases (Thomas et al., 2001c). Hence, diagnostic specificity and/or sensitivity should increase.
In yet a further embodiment of the invention, the type of and severity of the disease maybe diagnosed by comparing differential physiological effects from the same or different Cnps while being imaged with devices such as but not limited to functional magnetic resonance imaging (FMRI), position emission tomography (PET or SPECT), magnetoencephalography (MEG), electromyography (EMG) or electroencephalography (EEG).
It is understood by those skilled in the art that other similar set ups are possible and within the scope of the invention. It is only important that the Cnps exposure be relatively short and that the outcome measure is made during or after the exposure and the measures are compared. If the outcome device itself is perturbed by the Cnps, then synchronisation of the measurements with the exposure is needed. For example, EEG and EMG measurements would use devices that would pick up signal from this Cnps. However, as the Cnps design has short latency and longer refractory periods, where the magnetic fields are zero, measurements could be made during these periods. A-nalysis of Results
Outcome measures are then analysed in a manner relevant to the Cnps targeted tissue. In the example of the vestibular system, the measurements of the forceplate can be represented as a number of relevant parameters such as: total path, total area, total line and the total line can be broken down into the individual horizontal directions Table 1 and 3. Figure 4 shows typical measures of line (in metres) for three groups of human subjects: normals, patients with rheumatoid arthritis (RA) and patients with fibromyalgia (FM). Figure 5 shows how the outcome measures must be analysed such that the one sensitive to Cnps exposure is properly quantified. Here, the 'Romberg Quotient' shows that the vestibular system is perturbed by the PEMF but not the Sham exposure.
Classification of Patient Disease
The data is then appropriately analysed to separate patients into different disease categories dependent on how they responded to magnetic field exposure. Examination of Figure 5 and Figure 6 indicate that RA and FM differ in their response to Cnps and that each differ from the response of controls.
Patient Exposure Environment
Subjects under all embodiments are kept unaware of whether they are being exposed or sham exposed as placebo effects can be large in human subjects. Furthermore, exposure to other physical stimuli should be consistent for both sham and exposure. Particularly important is the exposure to light intensity. Figures 7A/B, 8A/B and 10 show the results from human subjects exposed to different light intensities. In the 9 normal subjects (mean age 26.4 (sd 2.6); 6 male, 3 female) exposed to a light intensity of 0.12W/m2, statistical analysis of the data (analysis of variance) indicated that there was a significant increase in standing movement during PEMF during eyes closed but not during eyes open. In a second experiment, 26 normal subjects (mean age 26.9 (sd 7.8); 13 male, 13 female) were exposed in an identical protocol except horizontal light levels were increased to 0.51 W/m2 (350 Lux). For this second group, standing balance was improved during PEMF exposure while subject's eyes were closed, a finding contrary to that found at the lower light intensity.
It is clear from these results that the outcome measure from exposure to magnetic fields is affected by light intensity during that exposure, a result consistent with the literature on the effects of extremely low frequency magnetic fields on animal behaviour (Prato et al, 2000). This suggests that the preferred application of the method of the present invention may include control of light intensities during Cnps exposure. Further, that during single or multiple Cnps exposure monitoring differential light intensities may improve the sensitivity and specificity of disease differentiation.
The present invention has numerous applications in various industries where the determination and severity of true pain and general disability be identified.
Examples
The examples are described for the purposes of illustration and are not intended to limit the scope of the invention.
Methods involved in magnetic field generation referred to but not explicitly described in this disclosure and examples are reported in the scientific literature and are well known to those skilled in the art.
Example 1 Diagnostic Discrimination of Rheumatoid Arthritis (RA) Patients from Fibromyalgia (FM) Patients and Both from Healthy Controls Based on Differential Effects of Pulsed Magnetic Fields (Cnps; 200μT) on Normal Standing.
Specific time varying pulsed magnetic fields (Cnps) have been shown to alter subjectively assessed animal and human behaviours, including pain perception. The differential response to specific pulsed magnetic fields was used on standing balance and other behavioural measures to separate normal control patients from patients with different diseases or pathologies.
Patients were recruited, 15 RA (mean ±SD 58±12.4; 5 male, 10 female) and 15 RA (mean ±SD 45±10.2; 15 female) from a university hospital outpatient rheumatology clinic. All patients met the most recent American College of Rheumatology (ACR) disease classification criteria. Also recruited were 15 healthy controls (mean ±SD 31±7.4; 7 male, 8 female) from among university students and personnel. Each subject was placed within 3 square Helmholtz coils (2m x 1.75m x 1.5m) (Thomas et al, 2000a), with each coil arranged orthogonal to the other two with the uniform magnetic field volume centred at head level for standing volunteers. (Figure 1, Figure 2). Subjects blind to study intent and exposure conditions stood with feet approximately 10cm apart on the centre of the 3D forceplate. All forceplate and Cnps (3D fluxgate magnetometer) values were continually digitally recorded at 20 samples per second. Each subject received four 2-minute exposure conditions (eyes open closed, sham/Cnps) in a random order. Standing balance was measured during each of the four exposures. A "Romberg Quotient" (RQ) was calculated for sham and Cnps exposures as the cumulative area of movement during normal standing balance with the "eyes closed" condition divided by the "eyes open" condition. Data was analysed using ANOVA and post hoc testing. Figure 3 shows a typical result in one patient with the pattern changing when the subject closes their eyes and when they are exposed to the Cnps. Figures 4, 5 and Figure 6 provide the raw data, the RQ and results for 3 parameter reductions of the raw data. With eyes open and during sham exposure, FM patients and controls appeared to have similar standing balance while RA patients had worse standing balance (Figure 4). With eyes closed, standing balance worsened for all three groups but moreso for RA and FM patients than for controls (Figure 4). The RQ was highest among FM patients (Figure 5, Figure 6). Mixed design analysis of variance on the centre of pressure (COP) measurements show a significant interaction of eyes open/closed and sham/Cnps conditions [F=8.78 (1,42), p<0.006). RQ of COP measurements improved significantly with Cnps exposure [F=9.5 (1,42), p<0.005] and COP path length showed an interaction approaching significance with clinical diagnosis [F=3.2 (l,28), p<0.09].
From these sets of experiments it was evident that RA and FM patients and healthy controls differed with respect to standing balance and the effect of the Cnps. The separation of RA patients from FM patients is of significant value as these patients are often given the wrong classification, ie. FM patients diagnosed incorrectly as RA patients and vice versa, especially in the initial manifestation of the disease. The ability to separate both these patients from normal controls especially FM from normal controls is extremely important in the scenario of workmen's compensation benefits. Among the medical community and among health insurers there is concern that individuals without true pain, fatigue or disability can feign pain, fatigue and/or disability and hence, be inappropriately classified as FM patients and receive compensation. It is also possible that true FM patients may not receive compensation as they cannot be objectively categorized. As the method of the present invention is entirely objective, it provides for the first time a measure which can be used to determine compensation rights.
Example 2 Assessment of Pain and Analgesia in Subjects Exposed to a Magnetic Field
Ratios of electrical current (mA time point/mA baseline) were applied to the web of the left thumb required to produce a subjective "moderate" pain rating in male and female university students (N^l l) while exposed to either a sham or pulsed magnetic field (Figure
11). A ratio greater than 1 may be interpreted as an indication of analgesia (or hypoalgesia), and less than 1, hyperalgesia. Individual subjects were randomly assigned to either an analgesia-inducing magnetic field (MF) exposure (N=6) or postural sway altering MF group (N=6). Sham and MF exposure trials were held at least one week apart and both experimenter and subjects were kept blind to the exposure conditions until the completion of the study (double-blinded). Electric current recordings at each time point (15-60 min) were divided by the baseline reading taken at time point 0 (not shown). Time point 15 was a second control time point, with exposures (sham or MF) starting at time point 25. The results' show a significant interaction between MF type (analgesia vs. postural sway) and exposure condition (sham vs. MF exposed) [FI,9 =8.9, PO.032, Eta2=0.64]. Error bars represent the S.E.M.
The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the above specific Examples. These Examples are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.
References
1. Barker A.T., Freeston I.L., Jalinous R., Jarratt J.A.. Magnetic stimulation of the human brain and peripheral nervous system: an introduction and the results of initial clinical evaluation. Neurosurgery 1987, 20, 100-109.
2. Prato F.S., Kavaliers M. and Thomas A.W. Extremely low frequency magnetic fields can either increase or decrease analgesia in the land snail depending on field and light conditions. Bioelectromagnetics 2000; 21:1-15.
3. Choleris E, Thomas A.W. Davaliers M, Prato F.S. A detailed ethological analysis of the mouse open field test: Effects of chlorodiazep oxide diazepam and extremely low frequency pulsed magnetic field. Neuroscience and Behavioural Reviews 2001.
4. Thomas A.W., Drost D.J., Prato F.S. 2001a. A magnetic field exposure and behavioural monitoring system. Bioelectromagnetics in press.
5. Thomas A.W. Drost D.J., Prato F.S. 2001b. Human subjects exposed to a specific pulsed magnetic field: effects on normal standing balance. Neurosciences Letters. 297: 121- 124.
6. Thomas A.W. White K.P. Drost D J. Cook CM., Prato F.S. 2001c. A comparison of rheumatoid arthritis (RA) and fibromyalgia (FM) patients and healthy controls exposed to a pulsed magnetic field: effects on normal standing balance. Neuroscience Letters. Accepted.
7. Prato F.S., Thomas A.W., Cook CM. 2001. Human Standing balance is affected by exposure to pulsed ELF magnetic fields: light intensity-dependent effects. NevroReport (in press). O 01/93948
19
Table of Romberg Quotients
(Mean ± l S.E.M.)
Br EyesClosed Measure
■**"•& Measure E τyesO-pen Measure
Light Intensity 0.12 W/m2 0.51 W/m2 Exposure : Sham PEMF Sham PEMF
I (VΛ±ocαa onU*r.-e*
Line : 1.29 ±0.14 1.78 ±0.24* 1.26 ±0.08 1.14 ±0.05* Area : 1.78 ±0.37 3.79 ±0.92* 1.78 ±0.21 1.44 ±0.12* Path : 1.64 ±0.14 1.88 ±0.24 1.66 ±0.10 1.69 ±0.13
* Significantly different between Light Intensities The interaction of Light Intensity and Exposure is significant (i.e. Line... F 3=11.8, P < 0.003).
TABLE 1
t"1
Figure imgf000021_0001
Λ relates to a significant difference (greater than, P < 0.05) between RA and FM within Pre- or Post-experiment testing, t relates to a significant difference (greater than, P < 0.05) between Pre- and Post-experiment testing.
Table of Results
(Mean ± 1 S.E.M.)
Rn _ EyesClosed Mea ure
Λ∑ Measure
EyesOpenKieaiure
Light Intensity: 0.12 W/m2 0.51 W/m2
Exposure : Sham PEMF Sham PEMF
Measure (Romberg Quotient, RQ)
Line : 1.29 +0.14 1.78 ±0.24* 1.26 +0.08 1.14 ±0.05*
Path : 1.64 ±0.14 1.88 ±0.24 1.66 ±0.10 1.69 ±0.13
* Significantly different between Light Intensities The interaction of Light Intensity and Exposure is SIGNIFICANT (LINE: F 3 = 11.8, p < 0.002).
Direction Sensitivity (Mean Axis Shift Difference (m), PEMF-Sham)
Light Intensity: 0.12 W/m2 0.51 W/m2
X axis : EO 4.805E-04+1.69E-03 9.517E-04±6.45E-03
EC 2.154E-05±3.06E-03 1.915E-03±7.22E-04*
Y axis : EO 5.670E-04±1.25E-03 1.242E-03±6.68E-04
EC 2.532E-04±1.60E-03 1.903E-04±8.40E-04
* Significantly different between Exposure condition only.
The interaction of Light Intensity and Exposure is not significant (P > 0.65).
TABLE 3
Figure imgf000023_0001
D O
Figure imgf000024_0001
Figure imgf000025_0001
6
O O y α.
Figure imgf000026_0001

Claims

Claims:
1. The use of a Cnps for the diagnosis of a disease condition in a subject.
2. The use of claim 1, wherein said use diagnoses the severity of said disease condition.
3. A method for the diagnosis of disease conditions in a subject, the method comprising:
- exposing a subject to a Cnps for a time effective to produce a physiological response;
- monitoring a selected physiological function; - evaluating a change in the selected physiological function;
- assessing the change in the selected physiological function; and
- classifying the subject into a disease category based on the assessment of the change in the selected physiological function.
4. The method of claim 3, wherein said Cnps is targeted to a specific tissue.
5. The method of claim 4, wherein said Cnps is selected to affect a specific physiological function.
6. The method of claim 5, wherein said physiological function is selected from the group consisting of a motor function and a cognitive function.
7. The method of claim 6, wherein said method is able to diagnose central nervous disorders.
8. The method of claim 7, wherein said method is able to diagnose a disease condition selected from the group consisting of Parkinson's disease, Huntington's chorea and Multiple Sclerosis.
9. The method of claim 6, wherein said method is able to diagnose peripheral disorders.
10. The method of claim 9, wherein said peripheral disorders are selected from the group consisting of rheumatoid arthritis, fibromyalgia, muscular dystrophy and general pain.
11. The method of claim 3, wherein said method is used to diagnose actual pain and fatigue compared to feigned pain and fatigue.
12. The method of claim 3, wherein said method is used to diagnose disability.
13. The method of claim 3, wherein a change in the selected physiological function is assessed obj ectively and/or subj ectively .
14. A method for the diagnosis and assessment of disease conditions in a subject, the method comprising:
- exposing a subject simultaneously to a selected Cnps and a first prescribed light intensity and frequency distribution while monitoring a selected physiological function;
- exposing said subject a second time simultaneously to said selected Cnps and a different light intensity of the same or different frequency distribution as said first prescribed light intensity while monitoring μ selected physiological function; and
- evaluating any change in the selected physiological function; - assessing said change in the selected physiological function; and
- classifying said subject into a disease category based on the assessment of the change in the selected physiological function.
15. A method for the diagnosis and assessment of disease conditions in a subject, the method comprising;
- exposing a subject to a first selected Cnps while monitoring a selected physiological function;
- exposing said subject a second time to a second selected Cnps while monitoring a selected physiological function; - evaluating any change in the selected physiological function;
- assessing said change in the selected physiological function; and - classifying said subject into a disease category based on the assessment of the change in the selected physiological function.
16. A method for the diagnosis of disease conditions in a subject, the method comprising; - evaluating a selected physiological function in a subject;
- exposing said subject to a selected Cnps;
- evaluating any change in the selected physiological function;
- assessing said change in the selected physiological function; and
- classifying said subject into a disease category based on the assessment of the change in the selected physiological function.
17. A method for the diagnosis of disease conditions in a subject, the method comprising;
- exposing a subject simultaneously to two or more selected Cnps while monitoring at least one selected physiological function; - evaluating any change in at least one selected physiological function;
- assessing said change in at least one selected physiological function; and
- classifying said subject into a disease category based on the assessment of the change in the at least one selected physiological function.
18. The method of any one of claims 14, 15, 16 or 17, wherein said Cnps is targeted to a specific tissue.
19. The method of any one of claims 14, 15, 16 or 17, wherein said Cnps is selected to affect a specific physiological function.
20. The method of claim 19, wherein said physiological function is selected from the group consisting of a motor function and a cognitive function.
21. The method of claim 20, wherein said method is able to diagnose central nervous disorders.
22. The method of claim 21, wherein said method is able to diagnose a disease condition selected from the group consisting of Parkinson's disease, Huntington's chorea and Multiple Sclerosis.
23. The method of claim 20, wherein said method is able to diagnose peripheral disorders.
24. The method of claim 23, wherein said peripheral disorders are selected from the group consisting of rheumatoid arthritis, fϊbromyalgia, muscular dystrophy and general pain.
25. The method of any one of claims 14, 15, 16 or 17, wherein said method is used to diagnose actual pain and fatigue compared to feigned pain and fatigue.
26. The method of any one of claims 14, 15, 16 or 17, wherein said method is used to diagnose disability.
27. The method of any one of claims 14, 15, 16 or 17, wherein a change in the selected physiological function is assessed objectively and/or subjectively.
28. The use of a Cnps for the assessment of feigned pain and/or fatigue in a subject.
29. A method for measuring pain, fatigue and/or disability in a subject, the method comprising: exposing a subject to a selected Cnps while simultaneously monitoring a selected physiological function; - comparing the physiological function with that of a suitable control; classifying the subject as experiencing pain, fatigue and/or a disability of feigning pain, fatigue and/or a disability.
30. A system for the diagnosis of disease conditions in a subject, the system comprising; - a coil array that produces a uniform magnetic field that perturbs a physiological function in a subject that is quantitatively or qualitatively assessed to generate a data set; - a data set representing a control; - wherein the two data sets are comparatively analyzed to classify the subject in a disease category.
31. A method for the diagnosis and assessment of disease conditions in a subject, the method comprising;
- comparing a data set representing the perturbation of a physiological function in a subject with a data set representing a control;
- classifying the subject in a disease category.
PCT/CA2001/000828 2000-06-08 2001-06-07 Diagnosis and classification of disease and disability using low frequency magnetic field designed pulses (cnps) WO2001093948A2 (en)

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Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001093948A2 (en) 2000-06-08 2001-12-13 Lawson Research Institute Diagnosis and classification of disease and disability using low frequency magnetic field designed pulses (cnps)
AU2001265729A1 (en) 2000-06-09 2001-12-17 Lawson Research Institute Device for magnetic and electric field shielding
US8047979B2 (en) * 2001-04-20 2011-11-01 Mclean Hospital Corporation Magnetic field treatment techniques
US7526071B2 (en) * 2007-04-06 2009-04-28 Warsaw Orthopedic, Inc. System and method for patient balance and position analysis
US8685093B2 (en) 2009-01-23 2014-04-01 Warsaw Orthopedic, Inc. Methods and systems for diagnosing, treating, or tracking spinal disorders
US8126736B2 (en) 2009-01-23 2012-02-28 Warsaw Orthopedic, Inc. Methods and systems for diagnosing, treating, or tracking spinal disorders
US8593141B1 (en) 2009-11-24 2013-11-26 Hypres, Inc. Magnetic resonance system and method employing a digital squid
US9326725B2 (en) * 2010-03-30 2016-05-03 Children's National Medical Center Apparatus and method for human algometry
US8970217B1 (en) 2010-04-14 2015-03-03 Hypres, Inc. System and method for noise reduction in magnetic resonance imaging
WO2014076698A1 (en) 2012-11-13 2014-05-22 Elminda Ltd. Neurophysiological data analysis using spatiotemporal parcellation
US10660558B2 (en) * 2013-03-29 2020-05-26 San Diego State University Research Foundation Apparatus and method for detecting clinically relevant changes in balance
US9882610B1 (en) * 2016-11-08 2018-01-30 Welch Allyn, Inc. Near field communication sensor system
US10806942B2 (en) 2016-11-10 2020-10-20 Qoravita LLC System and method for applying a low frequency magnetic field to biological tissues
WO2019060298A1 (en) 2017-09-19 2019-03-28 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement
US11717686B2 (en) 2017-12-04 2023-08-08 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement to facilitate learning and performance
US11478603B2 (en) 2017-12-31 2022-10-25 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement to enhance emotional response
US11364361B2 (en) 2018-04-20 2022-06-21 Neuroenhancement Lab, LLC System and method for inducing sleep by transplanting mental states
WO2020056418A1 (en) 2018-09-14 2020-03-19 Neuroenhancement Lab, LLC System and method of improving sleep
US11786694B2 (en) 2019-05-24 2023-10-17 NeuroLight, Inc. Device, method, and app for facilitating sleep

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3678337A (en) 1968-07-11 1972-07-18 Kurt Grauvogel Environmental control apparatus
US5066272A (en) 1990-06-29 1991-11-19 The Johns Hopkins University Magnetic nerve stimulator
GB2270000A (en) 1992-08-26 1994-03-02 Robert John Grace Magnetic field induction multi - pulse therapy.
US5935054A (en) 1995-06-07 1999-08-10 Loos; Hendricus G. Magnetic excitation of sensory resonances
US6234953B1 (en) 1996-06-06 2001-05-22 Lawson Research Institute Electrotherapy device using low frequency magnetic pulses

Family Cites Families (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2025237A (en) 1978-07-12 1980-01-23 Oliver J G Alleviation of bodily discomfort
JPS5955260A (en) 1982-09-21 1984-03-30 橋本　健 Electromagnetic treating device
DE8325466U1 (en) 1983-09-05 1986-11-27 Muenchinger, Bernd
US4825877A (en) 1984-04-20 1989-05-02 Kempe Frieder K Method of pain reduction using radiation-shielding textiles
US4583545A (en) * 1984-07-03 1986-04-22 Towe Bruce C Noninvasive biomagnesonic method of biocurrent measurement
DE3938920A1 (en) 1988-06-22 1991-05-29 Dragan Dipl Ing Susic Magnetic massage therapy device - has LF field coils and magnetic plates attached to body of patient
ATE253633T1 (en) 1989-08-22 2003-11-15 Hsc Res Dev Corp CYSTIC FIBROSIS GEN
CA2006319C (en) 1989-11-24 1995-01-24 Dragon Susic Magnetic massage therapy device
US5342410A (en) 1990-10-05 1994-08-30 Eric Braverman Apparatus and method for increasing the amplitude of P300 waves in the human brain
AU661789B2 (en) 1992-08-26 1995-08-03 Larkace Pty Ltd Magnetic field induction multi-pulse therapy
US5441528A (en) 1992-09-25 1995-08-15 Symtonic, S.A. Method and system for applying low energy emission therapy
US5621188A (en) 1994-05-06 1997-04-15 Lee; Sang C. Air permeable electromagnetic shielding medium
WO1996011723A1 (en) 1994-10-17 1996-04-25 Australasian Medical Technology Limited Devices and methods for implementation of pulsed electromagnetic field therapy
US5725471A (en) 1994-11-28 1998-03-10 Neotonus, Inc. Magnetic nerve stimulator for exciting peripheral nerves
US5690109A (en) 1995-06-23 1997-11-25 Govind; Rakesh Method of destructive, noninvasive hyperpyrexia of tissues and organisms utilizing nuclear magnetic resonance
US5707334A (en) * 1995-08-21 1998-01-13 Young; Robert B. Method of treating amygdala related transitory disorders
US5807272A (en) * 1995-10-31 1998-09-15 Worcester Polytechnic Institute Impedance spectroscopy system for ischemia monitoring and detection
AU735591B2 (en) 1996-08-15 2001-07-12 Neotonus, Inc. Transcranial brain stimulation
WO1998047565A1 (en) 1997-04-24 1998-10-29 Alexandr Andreevich Datchenko Method and device for medical influence on organs and systems of the organism
JP2002505596A (en) 1997-05-23 2002-02-19 トランサージカル，インコーポレイテッド MRI guided therapy device and method
CA2214296C (en) 1997-08-29 2005-11-29 Stanley A. Koren Apparatus for generating electromagnetic waveforms
US6198958B1 (en) * 1998-06-11 2001-03-06 Beth Israel Deaconess Medical Center, Inc. Method and apparatus for monitoring a magnetic resonance image during transcranial magnetic stimulation
ITPD980191A1 (en) 1998-08-04 2000-02-04 Getullio Talpo EQUIPMENT FOR TREATMENTS ON THE HUMAN BODY WITH VARIABLE MAGNETIC FIELDS.
US6427089B1 (en) * 1999-02-19 2002-07-30 Edward W. Knowlton Stomach treatment apparatus and method
PL194547B1 (en) 1999-06-14 2007-06-29 Med & Life Sp Z Oo Method of and apparatus for activating ions transport
US6719778B1 (en) * 2000-03-24 2004-04-13 Endovascular Technologies, Inc. Methods for treatment of aneurysms
AT409932B (en) 2000-03-27 2002-12-27 Mediscan Gmbh MAGNETIC FIELD GENERATOR FOR A COIL FOR TREATING HUMAN, ANIMAL OR VEGETABLE TISSUE
US6520903B1 (en) * 2000-05-18 2003-02-18 Patsy Yukie Yamashiro Multiple mode photonic stimulation device
WO2001093751A2 (en) * 2000-06-07 2001-12-13 New York University Diagnosis and treatment of thalamocortical dysrhythmia
WO2001093948A2 (en) 2000-06-08 2001-12-13 Lawson Research Institute Diagnosis and classification of disease and disability using low frequency magnetic field designed pulses (cnps)
AU2001265729A1 (en) 2000-06-09 2001-12-17 Lawson Research Institute Device for magnetic and electric field shielding
EP1326681B1 (en) 2000-10-20 2007-01-10 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Coil for magnetic stimulation
US6572528B2 (en) 2001-04-20 2003-06-03 Mclean Hospital Corporation Magnetic field stimulation techniques
EP1269913B1 (en) 2001-06-28 2004-08-04 BrainLAB AG Device for transcranial magnetic stimulation and cortical cartography
US7267644B2 (en) 2002-11-25 2007-09-11 Fralex Therapeutics, Inc. Portable electrotherapy device

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3678337A (en) 1968-07-11 1972-07-18 Kurt Grauvogel Environmental control apparatus
US5066272A (en) 1990-06-29 1991-11-19 The Johns Hopkins University Magnetic nerve stimulator
GB2270000A (en) 1992-08-26 1994-03-02 Robert John Grace Magnetic field induction multi - pulse therapy.
US5935054A (en) 1995-06-07 1999-08-10 Loos; Hendricus G. Magnetic excitation of sensory resonances
US6234953B1 (en) 1996-06-06 2001-05-22 Lawson Research Institute Electrotherapy device using low frequency magnetic pulses

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